The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

Abstract

Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time–concentration curve (AUC), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), Cmax, and t1/2 of PPF in PMs were 15.9 (12.5–19.2) µg·h/mL, 1.10 (0.796–1.40) µg/mL, and 12.8 (11.3–14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy.

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

“…The diagnosis of poisoning should be based on the observed effects on the human body, as well as the determination of whether the concentration of the xenobiotic in the blood is therapeutic, toxic or lethal. For a single oral therapeutic dose of PPF of 300-400 mg, the plasma concentrations ranged from 0.3 to 1.4 µg/mL [7]. At an oral dose of 150 mg every 6 h with a 4-day duration of administration, the reported steady state plasma concentration was up to 0.45 µg/mL [33].…”

“…PPF from a sustained-release tablet persists in the body longer and at a lower concentration, which ensures milder adverse effects. Several studies have shown that at therapeutic doses, poor metabolizers experience a significantly higher PPF concentration and elimination half-life [7]; thus, at therapeutic doses, which can become toxic, various adverse effects are observed. Zhender et al [8] observed nausea and vomiting at short-term higher therapeutic doses and the exacerbation of ventricular extrasystoles during long-term treatment.…”

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…However, it is noteworthy that these pharmacokinetic variations predominantly manifest as differences in heart rate, as opposed to other response phenotypes such as hypertension [32,33]. Various studies -including those by Thomas and Johnson [30] and Cunningham and Chapman [34] -have underscored this distinction. Within this domain, polymorphisms in the β adrenergic receptors ADRB1 and ADRB2, as well as in the G protein-coupled receptor kinase 5 gene GRK5 and G protein subunit beta 3 gene GNB3, have emerged as significant contributors [31,35].…”

“…[12] Section 2), but further mechanistic insight is needed. Propafenone, an antiarrhythmic drug, is also mentioned by the FDA as a potential risk for adverse events among CYP2D6 PMs, although there is not yet substantial evidence of a pronounced influence of CYP2D6 on its pharmacokinetic properties [30]. An overview of the polymorphic metabolism and transport as well as the effect of statins and P2Y1 / P2Y2 inhibitors is provided in Figs.…”